p66Shc--a longevity redox protein in human prostate cancer progression and metastasis : p66Shc in cancer progression and metastasis

Abstract

p66Shc, a 66 kDa proto-oncogene Src homologous-collagen homologue (Shc) adaptor protein, is classically known in mediating receptor tyrosine kinase signaling and recently identified as a sensor to oxidative stress-induced apoptosis and as a longevity protein in mammals. The expression of p66Shc is decreased in mice and increased in human fibroblasts upon aging and in aging-related diseases, including prostate cancer. p66Shc protein level correlates with the proliferation of several carcinoma cells and can be regulated by steroid hormones. Recent advances point that p66Shc protein plays a role in mediating cross-talk between steroid hormones and redox signals by serving as a common convergence point in signaling pathways on cell proliferation and apoptosis. This article first reviews the unique function of p66Shc protein in regulating oxidative stress-induced apoptosis. Subsequently, we discuss its novel role in androgen-regulated prostate cancer cell proliferation and metastasis and the mechanism by which it mediates androgen action via the redox signaling pathway. The data together indicate that p66Shc might be a useful biomarker for the prognosis of prostate cancer and serve as an effective target for its cancer treatment.

Fig. 1

A schematic organization of p66Shc. The p66Shc consists of a SH2 domain at the COOH-terminal, three major tyrosine phosphorylation sites and a threonine phosphorylation site within the central CH1 domain and a serine phosphorylation site (S138) in the PTB domain. It also contains a unique CH2 domain [110 amino acids] comprising the serine phosphorylation sites (S36 and S54) at the NH2-terminal. p66Shc also possesses a cytochrome c-binding region (CB) within the CH2-PTB domains

Fig. 2

A possible mechanism for the inhibitory effect of p66Shc on mitogenic signaling. Upon growth factor, e.g., EGF, stimulation, p66Shc competes with p52Shc/p46Shc isoforms for binding to the limited cellular pool of Grb2 and seizes the Grb2/SOS complex, but is unable to recruit SOS. Subsequently, serine 36 (S36) phosphorylation of p66Shc following tyrosine phosphorylation uncouples the association of p66Shc·Grb2 complex from EGFR via forming the nonproductive complex with Grb2, and thus may result in the dominant negative inhibition of p52Shc/p46Shc-mediated Ras-MAPK pathway

Fig. 3

A schematic representation for the possible role of p66Shc in oxidative stress-induced apoptosis. In the cytosol, p66Shc is phosphorylated at S36 upon oxidative stress and is mediated by the activation of p53, kinases and also due to modulation in the calcium ion concentration. The phosphorylated p66Shc is then translocated to the mitochondria by binding to a peptidyl-prolyl isomerase Pin1. In the mitochondrial intermembrane space, p66Shc associates to the mitochondrial super complex import machinery (TIM44, TIM20, TIM23 & mtHsp70) at the basal state, whereas upon oxidative stress signals mtHsp70 dissociates from TIM44 and facilitates the discharge of p66Shc (active) that has been associated with TOM-TIM complex. The monomeric p66Shc then interacts and oxidizes cytochrome c (cyt c) resulting in the generation of H2O2 via transferring electrons from reduced cytochrome c to oxygen and that increases the intracellular ROS levels. The increased intracellular ROS alters the mitochondrial membrane potential, leading to the opening of MPTP, swelling of mitochondria, release of cytochrome c and finally result in the mitochondrial fragmentation and apoptosis. The regulation of intracellular levels of ROS by S36-phosphorylated p66Shc is further mediated by inhibiting the transcriptional activity of the transcriptional factor FKHRL1

Fig. 4

p66Shc signaling and its novel mechanism regulated by androgens in prostate cancer cells. Oxidative stress including androgen depletion, UV and H2O2 induces the phosphorylation at S36 of p66Shc protein that leads to the increased production of ROS. The later mediates diverse biological functions, including cell proliferation, adhesion, migration and apoptosis. In prostate cancer cells, androgen (DHT) treatment also increases the ROS level via increasing the p66Shc protein level and decreasing the S36-phosphorylation of p66Shc, which lead to prostate cancer cell proliferation. p66Shc protein mediates androgen action on tumor progression. Upon stimulation by androgens, p66Shc is translocated to mitochondria via Ser-36 phosphorylation-independent manner resulting in the generation of ROS. ROS may then inhibit PTP, leading to corresponding RPTK activation and ERK/MAPK activation. ROS may also activate ERK/MAPK directly. Together, this activated signal can promote cell proliferation, survival as well as migration that collectively lead to tumor metastasis